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Epitomes Important Advances in Clinical Medicine

Pathology The Scientific Board ofthe California Medical Association presents thefollowing inventory of items ofprogress in pathology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonablyfirmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast ofthese items ofprogress in pathology that have recently achieved a substantial degree ofauthoritative acceptance, whether in their own field of special interest or another. The items ofprogress listed below were selected by the Advisory Panel to the Section on Pathology of the California Medical Association, and the summaries were prepared under its direction.

Reprint requests to Division of Scientific and Educational Activities, California Medical Association, PO Box 7690, San Francisco, CA 94120-7690

Tumor Necrosis Factor in Human Disease THE ACTIVE FORM of human tumor necrosis factor (TNF; cachectin) is a 157-residue (17-kilodalton) polypeptide cytokine. Its gene is located in the short arm of chromosome 6, near the gene of lymphotoxin (TNFO), another cytokine that shares some of its biologic activities. The best known sources of TNF are monocytes and macrophages, which secrete copious amounts of this protein on stimulation by endotoxin (lipopolysaccharide). In addition, T lymphocytes (CD4 and CD8), natural killer cells, Kupffer cells, microglia, and astrocytes appear to produce TNF. This cytokine, described in 1975, has been sequenced, cloned, and produced by recombinant techniques in humans in 1985 and in mice in 1986. Tumor necrosis factor can be measured by biologic assays, such as using its property to lyse fibroblasts of the L929 or WEHI 164/13 lines, or by immunologic assays using monoclonal antibodies of various specificities. The latter include enzyme-linked immunoassays (ELISA) and immunoradiometric assays (IRMA), which currently allow the detection of TNF in the range of 1 to 10 pg per ml. This high level of sensitivity will be useful in establishing the normal concentrations in various tissues that are probably of great physiologic importance. Receptors for TNF have been found in normal tissues including lungs, liver, kidneys, intestine, and skeletal muscle. Endothelial cells are among those with high-affinity receptors. Injected TNF has a short half-life in plasma of 6 to 7 minutes. Normal plasma or serum levels are below 15 pg per ml. The physiologic roles of TNF are the least known of its effects, partly because of the insensitivity of previous methods. Nevertheless, it appears that TNF is important at least in the inflammatory response and in tissue remodeling. In inflammation, TNF increases the chemotaxis of neutrophils and macrophages and the adhesion of leukocytes to endothelium, partly by increasing the expression of adhesion molecules such as intercellular-leukocyte and endothelialleukocyte adhesion molecules (ICAM and ELAM). Tumor necrosis factor is one of the cytokines that induce expression of the histocompatibility antigens, such as class I major histocompatibility complex in endothelial cells. It is likely that many of the TNF effects are not direct but are mediated through substances known to be stimulated by TNF. These a

include other cytokines (interleukin 1 and 6, granulocytemacrophage colony-stimulating factor, platelet-derived growth factor, and transforming growth factor-3), prostaglandins, and hormones (catecholamines, glucagon, and the like). In its tissue remodeling role, TNF promotes the proliferation of fibroblasts and perhaps smooth muscle. In endothelial cells it induces the expression of tissue factor and of the inhibitor of tissue plasminogen activator, as well as the synthesis of collagenases, proteases, and prostaglandins. It is also directly toxic to endothelial cells. It has been proposed that TNF induces wound healing, but there are conflicting data about its role in angiogenesis. The pathologic effects of TNF are better known. These include cachexia, septic shock, severe inflammatory reactions, and intravascular coagulation. Prolonged exposure to TNF alters several metabolic enzymes. In particular, it suppresses lipoprotein lipase and inhibits other lipid enzymes. The result is lipolysis, triglyceridemia, and glycogenolysis. In experiments, animals with long-term exposure to TNF become anorectic and depleted of protein and lipids. It is likely that anorexia and consequent cachexia in humans result from increased levels of TNF in various pathologic conditions including malignant neoplasms. The rapid intravenous administration of lipopolysaccharide-4 ng per kilogram of Escherichia coli endotoxinin humans has caused high peaks ( 240 pg per ml) of plasma TNF 90 to 180 minutes later, coinciding with fever, chills, myalgia, rigor, headache, nausea, and tachycardia. There was a simultaneous elevation of blood adrenocorticotropin, cortisol, and catecholamines. Leukocytosis occurred four hours later, when the plasma TNF level was almost undetectable. The symptoms, but not the rise in TNF levels, were prevented by administering a cyclooxygenase inhibitor. Similar symptoms, plus hypotension, have occurred in volunteers receiving a bolus of recombinant TNF. Larger doses of TNF in other species cause irreversible shock identical to the septic shock syndrome. That TNF is often responsible for septic shock is supported by a recent trial of anti-TNF monoclonal antibody. In 14 patients with septic shock, administering the antibody raised the blood pressure and prolonged survival. The experimental local effects of high tissue levels of TNF include hemorrhage, tissue

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necrosis, and abscesses. The systemic effects include disseminated intravascular coagulation. Increased levels of TNF in humans would likely result in similar alterations. The importance of TNF in human diseases was first reported in patients with gram-negative sepsis (purpura fulminans of meningococcemia). Also, it has a pathogenetic role in cerebral malaria, both human and experimentally induced. In both of these life-threatening conditions, elevated blood TNF levels on admission have correlated with an increased incidence of death or sequelae. Based on experimental data, the use of anti-TNF antibodies is promising as a therapeutic tool. Clinical trials of monoclonal antibody are underway in patients with gram-negative septic shock, cerebral malaria, and the OKT3-induced syndrome (in the context of transplantation). Other conditions associated with alterations of TNF in humans include rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, cystic fibrosis, graft-versushost disease, sarcoidosis, some parasitic infections (aside from malaria), septic arthritis, leprosy, and the acquired immunodeficiency syndrome. Patients with chronic heart disease have high serum levels of TNF, especially if they are cachectic. Such elevations in cachectic patients may be associated with activation of the renin-angiotensin system. In some conditions where blood TNF alterations are not detectable, dramatic changes may be found in other body fluids, such as in bronchial aspirates of patients with the adult respiratory distress syndrome. It appears that some neoplasms, including a human breast carcinoma and a mouse fibrosarcoma, secrete TNF in vitro. There is even a transplantable mouse tumor line genetically altered to continuously secrete human TNF. Thus, the possibility of using levels of blood TNF as markers of neoplastic activity has been raised. Some investigators have found TNF immunoreactivity in the serum of 50% of patients with ovarian, breast, and colon carcinoma, lymphomas, and myeloma; in 18% of patients in complete remission; and in 3 % of normal subjects. Other investigators have not detected TNF in cancer patients. Discrepant results of some TNF assays could be explained by the presence of TNF inhibitors, which would inhibit bioactivity but not immunoreactivity. Although the name "tumor necrosis factor" was derived from the observation that it produced lysis of a murine tumor, subsequent research on its putative antineoplastic effects has been generally disappointing, especially for human tumors. It is cytotoxic for some animal (such as L929 fibroblasts) and human tumor cell lines and does cause necrosis of some experimental neoplasms, but it seems to be ineffective in vivo against a good many human tumors, and toxicity is often reached before tumoricidal effect. Nevertheless, clinical trials with recombinant TNF are in progress. It is possible that the addition of other cytokines, or conventional chemotherapy, radiotherapy, or hyperthermia may potentiate the antineoplastic effects of tolerable doses of TNF. LUIS F. FAJARDO, MD Palo Alto, California GEORGES E. GRAU, MD

Geneva, Switzerland

REFERENCES Beutler B: The tumor necrosis factors: Cachectin and lymphotoxin. Hosp Pract (Off) 1990; 25:45-56 Beutler B, Cerami A: Cachectin: More than a tumor necrosis factor. N Engl J Med 1987; 316:379-385 Girardin E, Grau GE, Dayer JM, Roux-Lombard P, the J5 Study Group, Lambert

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89 PH: Tumor necrosis factor and interleukin-l in the serum of children with severe infectious purpura. N Engl J Med 1988; 319:397-400 Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P: Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 1987; 237:1210-1212 Grau GE, Taylor TE, Molyneux ME, et al: Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320:1586-1591 Tracey KJ, Vlassara H, Cerami A: Cachectin/tumour necrosis factor. Lancet 1989; 1:1122-1126

Pathologic Mechanism of Pulmonary Graft Rejection SINGLE-LUNG, DOUBLE-LUNG, and combined heart-lung transplantation have become life-saving therapeutic procedures for patients with end-stage pulmonary diseases. Graft rejection and infections compose the major posttransplant complications and can be diagnosed by fiberoptic bronchoscopy with transbronchial biopsy. The precise incidence of acute rejection in lung allograft recipients is unknown, but it has been estimated to be about 50% during the first two to three weeks after the procedure. Mild acute rejection is characterized by the development of interstitial edema and mild perivascular infiltrates by transformed lymphocytes, small lymphoid cells and eosinophils, endothelial cell swelling with occasional infiltration by lymphocytes (endothelialitis), and bronchial infiltrates by lymphoid cells and eosinophils or acute vasculitis, or both. These histopathologic features are usually patchy, and their diagnosis requires the examination of several histologic slides from each specimen. Moderate rejection is characterized by prominent perivascular and bronchial lymphoid infiltrates with extension of the inflammatory cells into the alveolar septa. In severe rejection, the lung undergoes hemorrhage and infarction with thrombosis of arteries and veins and vasculitis with fibrinoid necrosis. The diagnosis of chronic rejection in heart-lung transplant recipients remains controversial, but progressive pulmonary dysfunction due to bronchiolar and vascular complications has been described in about half of the long-term survivors. Obliterative bronchiolitis is the most important chronic complication in these patients. It can appear as early as 2 months after transplantation but usually results in respiratory symptoms at 11 to 12 months after the operation. In the early stages of obliterative bronchiolitis, the involved airways show ulceration and infiltration of their wall by inflammatory cells, followed by reepithelialization and intraluminal growth of granulation tissue with fibroblasts resulting in a scar that obliterates the airway lumen. Vascular complications include the development of an unusual form of accelerated atherosclerosis with concentric proliferation of myofibroblasts in the intima of pulmonary veins and arteries resulting in intimal sclerotic thickening. ALBERTO MARCHEVSKY, MD Los Angeles, California

REFERENCES Cagle PT, Truong LD, Holland VA, Lawrence EC, Noon GP, Greenberg SD: Lung biopsy evaluation of acute rejection versus opportunistic infection in lung transplant patients. Transplantation 1989; 47:713-715 Higenbottam T, Stewart S, Penketh A, Wallwork J: Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 1988; 46:532-539 Yousem SA, Tazelaar HD: Combined heart-lung transplantation, In Sale GE (Ed): The Pathology of Organ Transplantation. Boston, Mass, Butterworths, 1990, pp 153178

Tumor necrosis factor in human disease.

The Scientific Board of the California Medical Association presents the following inventory of items of progress in pathology. Each item, in the judgm...
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